Human cytomegalovirus (hCMV) may be the cause of salivary gland (SG) mucoepidermoid carcinoma (MEC), according to the results of a recent histological study.

Immunohistochemical staining using an antibody specific for hCMV-encoded IE1 protein, a marker for active hCMV infection, showed that the protein was found in 38 of 39 MEC samples, but in none of the normal glands or unaffected tumor regions, reported Michael Melnick, DDS, PhD, from the University of Southern California, and colleagues. Staining for antibodies against pp65 proteins, another marker for active hCMV infection, found that this group of proteins was expressed in tumor cells, but was absent in the adjacent unaffected region sample, normal glands, or tumor cells incubated in the absence of the primary antibody, the authors wrote in Experimental and Molecular Pathology. "Although still controversial, there is growing evidence that active hCMV infection is associated with a variety of malignancies, including brain, breast, lung, colon and prostate," the researchers wrote. "Given that hCMV is frequently resident in salivary gland ductal epithelium, we hypothesized that hCMV would be important to the pathogenesis of SG mucoepidermal carcinoma."

To explore the issue, specimens of human salivary gland MEC spanning seven years were randomly selected from the Oral Pathology Laboratory at Ohio State University. They were formalin-fixed, paraffin-embedded, tissue blocks from previous biopsies, allowing for routine histologic and immunohistochemical studies. A total of 39 tumors were selected for the study, including low-, intermediate-, and high-grade tumors from major and minor SGs and primary intraosseous tumors of the jaw. Minor salivary gland tissue from healthy patients was used as control tissue, and internal control samples were also available as unaffected tumor-adjacent SG tissue. "Prior work in laboratory has demonstrated the importance of the Cox-2, amphiregulin, activated EGFR and activated ERK pathway for CMV tumors in mouse models," wrote the authors. "(W)e postulated that we would see an overexpression (of these proteins) in human salivary gland MECs which exhibit hCMV IE1 and pp65 expressions." All components of this pathway were found in all grades of MECs. They were mostly absent in normal glands and in unaffected tumor-adjacent tissue.

"The evidence presented strongly implicates hCMV in the etiology and pathogenesis of human salivary gland MEC," wrote the authors. "All four prospective causal criteria for viruses and cancers are fully satisfied: (1) protein markers for active hCMV are present in 97% of MECs; (2) markers of active hCMV are absent in non-neoplastic SG tissue; (3) hCMV-specific proteins (IE1, pp65) are in specific cell types and expression is positively correlated with severity; (4) hCMV correlates and colocalizes with an upregulation of an established oncogenic signaling pathway. "Thus, the evidential support reported here and previously in a mouse model is strongly confirmatory of a causal relationship between hCMV and SG mucoepidermal carcinoma."

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The study was funded by the Oral Biology Fund of the Ostrow School of Dentistry of the University of Southern California.
The authors declared no conflicts of interest.

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